Development of a parenteral formulation of trimelamol, a synthetic S-triazine carbinolamine-containing cytotoxic agent.
Trimelamol is a synthetic s-triazine carbinolamine-containing agent exhibiting poor aqueous solubility and stability characteristics. The present studies were conducted to provide a stable parenteral dosage form of trimelamol, which could be used for clinical evaluation of the drug and also be manufactured on a commercial scale without undue drug decomposition occurring. Solubility and stability of trimelamol were found to increase in the presence of aqueous-polyethylene glycol (PEG) solutions of increasing average PEG molecular weight (up to mol wt = 1000); PEG 1000 (75%) in water provided the optimum formulation vehicle. In contrast to the optimum liquid formulation of the drug (detailed above) it was necessary to make various compromises to the formulation in terms of drug solubility and stability, because of the problems encountered in processing (e.g., sterile filtration, lyophilization, and reconstitution). Freeze-drying of the formulation extended the product shelf-life relative to the liquid formulation. Differential Scanning Colorimetry (DSC) studies, to determine the freeze-drying cycle parameters, showed that the freezing and melting characteristics of the trimelamol-PEG formulations were dependent upon the rate of cooling, as well as the concentration and average molecular weight of PEG used. The prototype containing 30 mg/mL trimelamol in a 50% PEG 3400-aqueous vehicle was found to be the optimal formulation for sterile filtration, lyophilization, and subsequent reconstitution. Through the use of in vitro techniques, the possibility of hemolysis occurring upon injection resulting from the inclusion of high molecular weight PEGs in the vehicle, was shown to be unlikely.
Gibson
M
M
Product Research and Development Laboratories, Cyanamid (GB) Limited, Gosport, Hants, UK.
Denham
A J
AJ
Taylor
P M
PM
Payne
N I
NI
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004355:Drug Stability; D005612:Freeze Drying; D006461:Hemolysis / Q000187:drug effects; D007263:Infusions, Parenteral; D011817:Rabbits; D012995:Solubility; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004337:Drug Carriers; D014227:Triazines; C049507:trimelamol